MIF/SCL3A2 depletion inhibits the proliferation and metastasis of colorectal cancer cells via the AKT/GSK-3β pathway and cell iron death

J Cell Mol Med. 2022 Jun;26(12):3410-3422. doi: 10.1111/jcmm.17352. Epub 2022 May 13.


This study investigated the mechanisms of migration inhibitory factor (MIF) and solute carrier family 3 member 2 (SLC3A2) in colorectal cancer progression. The levels of MIF and SLC3A2 expression in cells were measured by RT-qPCR. SW480 and SW620 cells were transfected with sh-MIF and sh-SLC3A2, respectively. MIF, SLC3A2, GPX4, E-cadherin and N-cadherin expression were detected by immunofluorescence (IF). CCK8 and Transwell assays were performed to detect cell proliferation and migration. Co-immunoprecipitation (CoIP) was used to measure the binding activity of MIF and SLC3A2. Finally, a nude mouse tumorigenicity assay was used to confirm the functions of MIF and SLC3A2 in colorectal cancer. Results showed that the levels of MIF and SLC3A2 expression were up-regulated in colorectal cancer cells. Inhibition of MIF or SLC3A2 expression prevented cell proliferation, migration, epithelial-mesenchymal transition (EMT) and invasion. In addition, knockdown of MIF and SLC3A2 promoted iron death in SW480 and SW620 cells. CoIP results showed that MIF and SLC3A2 directly interact with each other. Knockdown of both MIF and SLC3A2 inhibited tumour growth and metastasis via the AKT/GSK-3β pathway in vivo. The Akt/GSK-3β pathway was found to participate in regulating MIF and SLC3A2 both in vivo and in vitro. MIF and SLC3A2 might be potential biomarkers for monitoring the treatment of colorectal cancer.

Keywords: Akt/GSK-3β signalling; SLC3A2; colorectal cancer; macrophage migration inhibitory factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / metabolism
  • Colorectal Neoplasms* / pathology
  • Epithelial-Mesenchymal Transition
  • Glycogen Synthase Kinase 3 beta* / genetics
  • Glycogen Synthase Kinase 3 beta* / metabolism
  • Iron* / metabolism
  • Macrophage Migration-Inhibitory Factors* / genetics
  • Macrophage Migration-Inhibitory Factors* / metabolism
  • Mice
  • Proto-Oncogene Proteins c-akt* / genetics
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Signal Transduction


  • Macrophage Migration-Inhibitory Factors
  • Iron
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt